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Towards the Clinical Implementation of ESC-derived Cardiac Cells

Review of “Human embryonic-stem-cell-derived cardiomyocytes regenerate non-human primate hearts” from Nature by Stuart P. Atkinson

Transplantation of human embryonic stem cell-derived cardiomyocytes (hESC-CMs) has the potential to support heart regeneration [1] and small-animal studies have shown this to be a feasible procedure with good outcome [2]. However, the production and handling of CMs at a clinical scale and their transplantation into a suitable model system remains relatively unexplored. Now, the group of Charles E. Murry at the University of Washington, Seattle, USA have studied the production, preservation and subsequent transplantation of hESC-CMs into non-human primate hearts in a model of myocardial ischaemia and have investigated the ability of these exogenously delivered hESC-CMs to engraft and electrically couple to host myocardium [3].

Due to the amount of cells required (an estimated 1 x 109 cells, extrapolated from small animal studies), cryopreservation of CMs is required, a process which the group validated in a mouse model, finding cells to be utile after a freeze/thaw cycle. Generation of hESC-CMs utilised a well-established monolayer protocol [4] which produced a population of cells which were around 73% positive for cardiac Troponin T (cTnT) and displayed spontaneous beating. Cells were then delivered into the infarct region of pigtail macaques, which represented no more than 10% of the left ventricle, with graft size averaging 40% of infarct volume. At this time, 98% of cells expressed sarcomeric protein -actininin, indicative of cardiomyocytes, which matured with time after transplantation; increased myofibril alignment, sarcomere registration and cardiomyocytes diameter. Grafted cells displayed frequent interactions with host cells and grafts became perfused by host vessels, which the authors contend is the first evidence of perfusion and long term viability of large hESC-CM grafts.

The researchers then assessed electro-magnetic coupling through ex vivo fluorescent imaging, finding electrical activation in each of the hESC-CM treated hearts. 100% of the visible hESC-CM grafts in every monkey showed electromechanical coupling to the host heart while the hESC-CM grafts retained 1:1 coupling to host myocardium during atrial pacing. However, all macaques that received hESC-CMs showed arrhythmias (premature ventricular contractions and runs of ventricular tachycardia) although all animals remained conscious and in no distress during these periods of arrhythmia. Variable responses in the functionality of the left ventricle after hESC-CM grafting did however confound any attempt to derive significant effects of the transplantation.

This important large-animal model has demonstrated extensive remuscularization of infarcts, complete electrical coupling and normal response to pacing; all suggesting that scale up to trials in human beings is feasible. The arrhythmias observed do require further studies to confirm possible mechanisms, but may be due to the differences in size and heart rate for the macaque monkey as compared to the small-animal models used previously. The authors hope that studies using larger numbers of animals and larger infarct sizes will confirm their exciting findings in the future, bringing closer the reality of human CM transplantation as a viable clinical choice for treating heart failure.
References

  1. Laflamme MA and Murry CE Heart regeneration. Nature 2011;473:326-335.
  2. Fernandes S, Naumova AV, Zhu WZ, et al. Human embryonic stem cell-derived cardiomyocytes engraft but do not alter cardiac remodeling after chronic infarction in rats. J Mol Cell Cardiol 2010;49:941-949.
  3. Chong JJ, Yang X, Don CW, et al. Human embryonic-stem-cell-derived cardiomyocytes regenerate non-human primate hearts. Nature 2014;510:273-277.
  4. Laflamme MA, Chen KY, Naumova AV, et al. Cardiomyocytes derived from human embryonic stem cells in pro-survival factors enhance function of infarcted rat hearts. Nat Biotechnol 2007;25:1015-1024.